Integrins comprise a large family of heterodimeric receptors that mediate fundamental adhesion dependent cellular processes such as migration, proliferation, and survival, and are found in many animal species, ranging from sponges to mammals. Dysregulation of these receptors underlies many pathologies including neoplasms, tumor metastasis and cardiovascular disease. Integrins differ from classic receptors in that they normally exist in a low affinity state until activated through inside-out signaling. The latter processes produces conformational changes in the extracellular ligand binding site(s), allowing the integrin to engage ligands in a divalent cation-dependent manner. The liganded integrin then transmits signals to the cell interior that are also associated with tertiary and quaternary changes in the receptor and which vary depending on the nature of the ligand. Thus a ligand and a ligand-mimic may not produce the same functional effect, which complicates a better understanding of integrin-triggered cellular responses and hampers ongoing efforts to target these receptors therapeutically. The nature of the conformational changes that accompany these activation and signaling functions in a whole integrin are unknown, due in large part to the lack of experimental information on the domain structure of a whole integrin. The physicochemical properties of integrins, being large, transmembrane, heterodimeric and glycosylated proteins have so far precluded direct structural investigations of the whole molecule by currently available high-resolution methods. We have now achieved a milestone that forms a basis for this new grant application. We have obtained high quality crystal forms of the whole extracellular region of alphaVbeta3 integrin, a receptor known to play major roles in angiogenesis, cancer, restenosis and bone remodeling. The alphaVbeta3 crystals diffract to a very good resolution. This allowed us to carry out X-ray diffraction analysis, obtain an electron density map that was used to build a 3-D model of this integrin. We now propose to obtain a higher resolution model of this structure, solve the structure of this integrin in complex with a monomeric RGD peptide or a physiologic ligand to define the nature of the associated conformational changes, and determine the functional correlates of key features elucidated from the crystal structure using cell biology, genetic and biochemical approaches. Results from the proposed studies will stimulate new lines of inquiry into integrin biology at the cellular and organismal levels and are expected to have a profound impact on structure-based drug design with applications for treatment or prevention of several diseases including cancer and heart disease.